natural killer-cell therapy for acute myeloid leukemia

Conditions: Acute Myeloid Leukemia Refractory; Acute Myeloid Leukemia, Relapsed, Adult

Summary: this study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia exploiting administration of ex vivo-generated allogeneic natural killer (nk) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo il-2 cytokine support.

this study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia (aml) exploiting administration of ex vivo-generated allogeneic natural killer (nk) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo il-2 cytokine support. this is a prospective phase i/iia study. the first phase is a il-2 dose-escalating safety study in twelve patients. the second phase of the study is designed as a simon's optimal two-stage single-arm phase iia study, comprising seventeen patients. prior to nk cell infusion, all patients will receive cyclophosphamide and fludarabine (cy/flu) based lymphodepleting chemotherapy. on day 0, all patients will receive a fixed dose of 1.0-3.0 x 10\^9 allogeneic umbilical cord blood-derived nk cells (ucb-nk cells). these cells are generated ex vivo from cd34+ hematopoietic progenitor cells obtained from an allogeneic ucb unit. in phase i of the study patients will receive ucb-nk cells without subcutaneous (sc) il-2, with lower dose sc il-2 or with higher dose sc il-2 (n=3 per treatment group, n=6 in the highest tolerable dose). after establishing the safety of ucb-nk cells combined with sc il-2, we will continue with phase iia of the study, with ten patients in the first stage (including the six patients from phase i with comparable il-2 dose) and if clinical efficacy is achieved an additional seven patients in the second stage.

Eligibility criteria:
inclusion criteria: * aml patients (de novo and secondary) or patients with mds excess blasts-2 according to who criteria 2016, who have stable disease or non-rapidly progressive disease with or without disease controlling medication who are (at time of inclusion) ineligible for allo-sct. * patients may belong to any of the following categories: * relapsed/refractory disease after treatment with intensive chemotherapy, hypomethylating agents, targeted agents, autologous or allo-sct (at least 6 months ago) and dli * newly diagnosed, untreated patients ineligible for allo-sct other inclusion criteria: * age ≥ 18 years * who performance 0-2 * life expectancy of \> 4 months * written informed consent * hydrea is allowed as pre-treatment to control blast count until day -3 * other disease controlling medication is allowed until day -7 exclusion criteria: * progressive disease according to eln criteria in case of previous therapy * patients on immunosuppressive drugs or active gvhd * patients with active infections (viral, bacterial or fungal); acute anti-infectious therapy must have been completed within 14 days prior to study treatment * severe cardiovascular disease (ctcae iii-iv) * severe pulmonary dysfunction (ctcae iii-iv) * severe renal dysfunction (ctcae iii-iv) * severe hepatic dysfunction (ctcae iii-iv) * severe neurological or psychiatric dysfunction (ctcae iii-iv) * patients on concurrent chemotherapy or interferon-alpha treatment * pregnancy or breastfeeding

Keywords: natural killer cells acute myeloid leukemia cellular immunotherapy